1. Technical Field
The present technology pertains generally to medical imaging methods, and more particularly to methods for pH-weighted magnetic resonance imaging using amine chemical exchange saturation transfer echo planar imaging (CEST-EPI).
2. Background Discussion
Pronounced changes in tissue pH may be observed with numerous injurious conditions in humans, including cancer growth, stroke hypoxia, and seizure activity such as epilepsy. For example, it has been observed that tissue acidosis contributes directly to a microenvironment that is hospitable to many cancers. Various studies have reported that tumor cells have alkaline intracellular pH values (7.1-7.6 compared with 7-7.2 in normal tissues) and acidic extracellular pH values (6.2-6.9 compared with 7.3-7.4 in normal tissues). This decrease in extracellular pH is thought to be directly due to tumor size and altered blood flow, leading to increased hypoxia. This lack of oxygen increases glycolysis resulting in the accumulation of carboxylic acid and/or lactic acid in the extracellular spaces. Additionally, active transport of protons out of tumor cells to maintain high intracellular pH results in further decreases in pH within the immediate environment. These effects are further exacerbated by a diminished buffering capability of tumor interstitial fluid along with limited elimination of lactic acid and protons into the blood vasculature.
The increase in extracellular acidity comes with dramatic consequences, as it can be directly linked to the degree of tumor aggressiveness. In particular, a decrease in extracellular pH can result in decreased immune function, increased chromosomal rearrangements, increased tumor invasion, and increased angiogenesis through elevated VEGF and platelet-derived endothelial cell growth factor.
The decrease in extracellular pH also results in resistance to various forms of therapy including resistance to radiation therapy and specific chemotherapies. Thus, a non-invasive imaging method for spatially identifying regions of low tissue pH may be invaluable for early identification of malignant transformation, predicting early treatment resistance, as well as potentially detecting early tumor invasion, proliferation, angiogenesis, hypoxia, genetic mutations, and altered immune response.
Some positron emission tomography (PET) imaging techniques have shown sensitivity to pH, but this requires the use of an exogenous radiotracer. Similarly, some paramagnetic CEST contrast agents can be sensitive to pH, but this also requires the use of exogenous agents that are not currently FDA approved for humans.
Accordingly, there is a need for the development methods for non-invasively measuring altered, typically decreased, tissue pH in patients that does not require the use of exogenous contrast agents. There is also a need for fast, high spatial resolution pH imaging techniques for clinical evaluation of cancers, including gliomas. The present technology satisfies these needs.